Immuno -pharmacology of Transplantation. Important Points to Note --T cell response is responsible for organ rejection --Inhibition of CD4 T cell activation is a major strategy to prevent rejection --Calcineurin is the major signal transducer of calcium signaling in T cells
--Anti-CD3 antibodies (Orthoclone) prevents TCR binding to MHC-peptide complex, but also depletes T cell population.
Mechanism of action of Cyclosporine (CsA) and FK506 is very unique. They don’t bind target enzyme directly, but must complex with an intermediate cellular protein. Both drugs bind immunophilin, and the drug-immunophilin complex is the inhibitor.
Calcineurin is a protein phosphatase that transduces calcium signals from the cytosol to the nucleus via a transcription factor called NFAT.
Since CsA-cyclophilin and FK506-FKBP complexes inhibit calcineurin, NFAT remains quiescent.
Instead, the Rapamycin-FKBP complex binds TOR, which regulates transcription/translation of genes required for T cell activation.
Rapamycin induces T cell tolerance to the graft, so you may be able to eventually stop the drug. With CsA and FK506 you block T cell activation but also proliferation, which prevents the development of tolerance to the graft and requires lifetime use of the drugs.